Combination chemotherapy is the standard of care for most disseminated cancers. Yet, despite the widespread use of these drug regimens, the basic mechanisms of combinatorial efficacy remain poorly understood. A common rationale for multi-drug administration in cancer is to evade spontaneous resistance to single agents, a model borrowed from microbiology, whereby multiple independent mutations in distinct drug targets are necessary to develop resistance (Luria, S. E. & Delbruck, M. Genetics 28, 491-511 (1943); Newcombe, H. B. & Nyholm, M. H. Genetics 35, 603-611 (1950); Law, L. W. Nature 169, 628-629 (1952); Law, L. W. Cancer Research 12, 871-878 (1952); Frei, E., 3rd et al. Blood 13, 1126-1148 (1958)). These arguments are well substantiated in drug resistant bacteria (Blanchard, J. S. Annual Review of Biochemistry 65, 215-239 (1996); Telenti, A. et al. Lancet 341, 647-650 (1993); Brossier, F., et al., Journal of Clinical Microbiology 48, 1683-1689 (2010)), but insufficient to explain the frequency of single mutations conferring multi-drug resistance in human cancers (Mullighan, C. G. et al. Science 322, 1377-1380 (2008); Chen, G., et al., Cancer Research 54, 4980-4987 (1994); Lau, D. H., et al. Cancer Research 51, 5181-5187 (1991); Chen, G. K., British Journal of Cancer 83, 892-898, (2000)). Synergistic cytotoxicity is also argued as a rationale for combination therapy (Goldin, A. & Mantel, N. Cancer Research 17, 635-654 (1957); Borisy, A. A. et al. Proc Natl Acad Sci USA 100, 7977-7982 (2003); Lehar, J. et al. Nature Biotechnology 27, 659-666 (2009)), but cell-intrinsic drug synergy frequently fails to predict efficacy in clinical trials (Goldin, A. & Mantel, N. Cancer Research 17, 635-654 (1957); Greco, W. R., et al., Journal of the National Cancer Institute 88, 699-700 (1996); Ramalingam, S. S. et al. Clinical Cancer Research 14, 3456-3461 (2008); Goldin, A., et al., Annals of the New York Academy of Sciences 76, 932-938 (1958)).
Thus a need exists for improved methods for understanding the mechanisms of combinatorial efficacy of drugs.